Coordinate regulation of gonadotropin-releasing hormone neuronal firing patterns by cytosolic calcium and store depletion

Elevation of cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in excitable cells often acts as a negative feedback signal on firing of action potentials and the associated voltage-gated Ca(2+) influx. Increased [Ca(2+)](i) stimulates Ca(2+)-sensitive K(+) channels (I(K-Ca)), and this, in turn, hyperpolarizes the cell and inhibits Ca(2+) influx. However, in some cells expressing I(K-Ca) the elevation in [Ca(2+)](i) by depletion of intracellular stores facilitates voltage-gated Ca(2+) influx. This phenomenon was studied in hypothalamic GT1 neuronal cells during store depletion caused by activation of gonadotropin-releasing hormone (GnRH) receptors and inhibition of endoplasmic reticulum (Ca(2+))ATPase with thapsigargin. GnRH induced a rapid spike increase in [Ca(2+)](i) accompanied by transient hyperpolarization, followed by a sustained [Ca(2+)](i) plateau during which the depolarized cells fired with higher frequency. The transient hyperpolarization was caused by the initial spike in [Ca(2+)](i) and was mediated by apamin-sensitive I(K-Ca) channels, which also were operative during the subsequent depolarization phase. Agonist-induced depolarization and increased firing were independent of [Ca(2+)](i) and were not mediated by inhibition of K(+) current, but by facilitation of a voltage-insensitive, Ca(2+)-conducting inward current. Store depletion by thapsigargin also activated this inward depolarizing current and increased the firing frequency. Thus, the pattern of firing in GT1 neurons is regulated coordinately by apamin-sensitive SK current and store depletion-activated Ca(2+) current. This dual control of pacemaker activity facilitates voltage-gated Ca(2+) influx at elevated [Ca(2+)](i) levels, but also protects cells from Ca(2+) overload. This process may also provide a general mechanism for the integration of voltage-gated Ca(2+) influx into receptor-controlled Ca(2+) mobilization.